There has been a substantial increase in the incidence of prostate cancer recently, particularly in the proportion of patients presenting with early stages of the disease. Despite this shift toward early diagnosis, prostate cancer remains the second most common cause of death from cancer, with approximately 25% of all prostate cancer patients ultimately dying from metastatic disease. In contrast to organ-confined disease, there is still no curative treatment for metastatic prostate cancer. Moreover, in spite of better understanding of the clinical and biologic aspects of this disease, the median survival of patients with metastatic prostate cancer has not changed in the last five decades and ranges from 24 to 36 months.

The first line of treatment for metastatic prostate cancer relies primarily on the suppression of gonadal androgens. While androgen deprivation represents an extremely effective palliative treatment for patients with metastatic disease, a survival benefit for this treatment has never been properly demonstrated in randomized trials. Current methods for gonadal androgen ablation involve either surgical castration or medical castration with gonadotropin-releasing hormone (Gn-RH) analogues. Orchiectomy and Gn-RH analogues have shown comparable efficacy in terms of subjective and objective response, time to progression, and survival. The major palliative effects of endocrine treatment in prostate cancer include decreased pain and urinary symptoms and improved performance status and quality of life. Unfortunately, almost all patients with metastatic disease treated with gonadal suppression eventually show disease progression. The median time to clinical progression of cohorts of patients treated in large clinical trials by different forms of hormonal therapy have ranged from 12 to 18 months. Following disease progression, the survival rates of cohorts of patients with metastatic prostate cancer entered in clinical trials have remained relatively stable, and no treatment has been shown to improve survival in this group of patients.

Combined androgen blockade involves the use of an antiandrogen in combination with any method of castration. The concept of Combined androgen blockade was derived from laboratory observations that following gonadal suppression, incorporation of androgens into prostatic cells remained significant due to continuous production of adrenal androgens and their conversion to dihydrotestosterone. Further, it was suggested that following castration, prostate cancer cells could adapt to very low (castrate) levels of testosterone, which would continue to induce a clinically significant tumor growth. It was therefore implied that blocking the residual androgens at the level of the cancer cells by androgen receptor antagonists would result in better control of tumor growth. However, the actual role of residual testosterone and adrenal androgens in disease progression following androgen ablation treatment has never been conclusively demonstrated. Tumor recurrence is an inevitable event with any type of endocrine manipulation and is believed to be associated primarily with progressive changes in the tumor cells and the development of a hormone refractory state.

The scientific accuracy and significance of the concept of maximal androgen blockade has been challenged by many over the past 15 years and remains controversial. The consequences of Combined androgen blockade both in clinical research and in daily clinical care, however, have been substantial. There have been a large number of clinical trials launched to investigate the potential benefit of Combined androgen blockade, accruing almost 8000 patients over the past 15 years. This large body of data provides the critical test of the Combined androgen blockade hypothesis. Widespread use of expensive combined endocrine regimens has no doubt contributed significantly to the astronomic increase in medical care costs of patients with metastatic prostate cancer. Thus, in view of the important clinical, biologic, and economic implications of the concept behind combined endocrine regimens, it is critical to evaluate the extensive clinical data accumulated over the past several years from research in this area. The studies conducted thus far are reviewed in the following sections.

Overview of Clinical Trials

Observations in Patient Subsets (Minimal Disease)

Meta-analyses

In 1995, the Prostate Cancer Trialists’ Collaborative Group (PCTCG) reported on the first meta-analysis conducted to increase the statistical power of individual prostate cancer trials. Their report included data from 22 randomized trials comparing Combined androgen blockade to castration monotherapy in 5710 patients. To achieve an intention-to-treat analysis, complete individual data on each randomized patient were requested from the investigators. Hazard ratio was calculated separately for every trial based on the raw data and then combined to all other trials using log rank statistics. The meta-analysis showed a 2.1% difference in mortality in favor of Combined androgen blockade treatment (6.4% reduction in annual odds of death), which is not statistically significant. The results were not influenced by separate analysis for the different antiandrogens (flutamide, nilutamide, or cyproterone acetate) or by the different methods of gonadal ablation.

Two separate meta-analyses evaluated the effects of flutamide and nilutamide in the context of Combined androgen blockade. Caubet et al. selected nine published trials with adequate information while Bertagna et al. included only trials that compared orchiectomy plus nilutamide to orchiectomy alone (N = 7). While both reports suggest a significant survival advantage for the Combined androgen blockade approach, there are major concerns about these analyses regarding criteria for study selection, limited number of patients, short follow-up, and the use of published versus raw data analysis. Such methodologic problems reduce the significance of these reports.

Adverse Effects and Quality of Life

Summary

There has been a large body of data accumulated over the years on clinical trials evaluating the concept of Combined androgen blockade as the primary treatment for metastatic prostate cancer. There are significant differences in study design, size of trial, choice of agents, methods of evaluation, and, to a lesser extent, patient selection criteria. Of 27 trials involving approximately 8000 patients, three were reported to result in a statistically significant prolonged survival. The advantage in median survival represented in these three trials ranged from 3.7 to 7 months (12 to 25% improvement) . Other clinical trials with similar design showed no significant improvements. Despite the differences between studies, data from a meta-analysis including all studies (PCTCG) indicate that the treatment effect of Combined androgen blockade is clinically negligible. Further, neither the type of gonadal ablation (surgical versus medical) nor the choice of nonsteroidal antiandrogen has an impact on outcome. Trials employing cyproterone acetate, however, show a trend of worse survival in the Combined androgen blockade arm.

The data outlined in this chapter demonstrate that Combined androgen blockade versus monotherapy trials have failed to show consistent and significant improvement in patient survival. Further, there is no evidence that Combined androgen blockade is associated with a favorable outcome in quality of life.

The vast majority of patients had metastatic disease, largely stage D2, but several trials included patients with nonmetastatic disease. Many trials included small numbers of patients and insufficient follow-up, resulting in a

lack of statistical power to appropriately test the primary hypothesis. Relative efficacy was assessed by comparing treatment arms with respect to survival, disease progression, and response. Overall survival (death from any cause) is the most accurate and most commonly used outcome parameter and will be the focus of this discussion. Most authors also compared the results of progression-free survival between Combined androgen blockade and monotherapy.

TABLE. Large Randomized Trials Comparing Combined Androgen Blockade to Monotherapy

N = number of patients; %M = percentage of patients with established metastatic disease; progression-free survival = progression-free survival; OS = overall survival; N/A = not available; f/u = follow-up; Gn-RH = gonadotropin-releasing hormone; cyproterone acetate = cyproterone acetate * > 100 patients/treatment arm

Most of the trials, including the largest one (INT-0105), reported no significant difference in survival between Combined androgen blockade and monotherapy while only three studies showed a statistically significant advantage for the use of Combined androgen blockade. As is shown in Table 36-1, for every positive trial (Combined androgen blockade survival benefit) there are one to five identically or similarly designed studies with negative results.

Gn-RH Analogue plus Antiandrogen versus Gn-RH Analogue Alone

Twelve studies (N = 3733 patients) used Gn-RH analogues as the method of castration in both treatments arms. The first published large-scale, prospectively randomized, clinical trial was the National Cancer Institute (NCI)-sponsored INT-0036, published by Crawford et al. in 1989. This trial compared daily subcutaneous 1 mg leuprolide injections plus flutamide versus leuprolide and placebo in 617 patients. The median overall survival for patients treated with Combined androgen blockade and monotherapy was 35 and 29 months, respectively (two-sided p = .03).

While the results of INT-0036 supported significant survival advantage for the Combined androgen blockade arm, it remains possible that this result is due to factors not necessarily central to the Combined androgen blockade concept. One explanation is that the difference in outcome might be related to the effect of Combined androgen blockade on the flare phenomenon. This phenomenon represents the transient increase in gonadotropins and testosterone levels during the early stages of Gn-RH analogue treatment. Although of relatively short duration, and despite the lack of clinical evidence to support the hypothesis, this hormonal stimulatory phase could have resulted in acceleration of tumor growth with consequent long-term effects on progression-free and overall survival rates. The clinical flare has been shown to be effectively counteracted by concomitant administration of antiandrogens. In support of this hypothesis is the evidence from INT-0036, which suggested that during the first 12 weeks of treatment there was a favorable trend in pain control, improvement in performance status, and changes in acid phosphatase in patients randomized to the Combined androgen blockade arm. In a recently published study by Bono et al. for the Italian Leuprorelin Group, administration of flutamide for 2 weeks in combination with leuprolide (to counteract the flare in the monotherapy arm) resulted in no difference in overall survival between treatment arms compared to standard Combined androgen blockade.

Another explanation for the results of INT-0036 is related to possible compliance problems associated with the use of daily subcutaneous administration of leuprolide, the only preparation available at the time of the study. Significant compliance problems exist with daily injections, resulting in inadequate testicular suppression; this could explain the advantage observed for those receiving leuprolide with flutamide over leuprolide alone. Since INT-0036 was not designed to include a routine evaluation of serum testosterone, this argument could not be effectively excluded.

Table Large Randomized Trials Comparing Combined Androgen Blockade to Monotherapy also illustrates seven large studies comparing a Gn-RH analogue with and without an antiandrogen, including three studies employing cyproterone acetate in the combined regimen. Two studies in this category deserve elaboration. Tyrell et al. randomized 557 patients between goserelin and flutamide versus goserelin alone. Crawford et al. compared leuprolide plus nilutamide versus leuprolide plus placebo (N = 411 patients). In both studies, there was no statistically significant difference in survival. None of the other studies demonstrated a survival advantage for the combination arm; interestingly, one of the studies actually showed shorter survival in the combination arm.

Orchiectomy plus Antiandrogens versus Orchiectomy Alone

Orchiectomy may still be considered the “gold standard” for gonadal ablation. The use of bilateral orchiectomy eliminates the possibility of a flare reaction and compliance problems as alternative explanations for the results observed with the Gn-RH analogues.

Dijkman et al. reported on a multinational, prospectively randomized, placebo-controlled study comparing orchiectomy plus nilutamide to orchiectomy alone. The results showed a small but significant difference in median survival (27.3 versus 23.6 months, p = .032), observed at 8.5 years follow-up, in favor of the Combined androgen blockade regimen.

All other large studies comparing orchiectomy and orchiectomy plus antiandrogen reported negative results. An Australian multicenter trial reported by Zalcberg et al. compared bilateral orchiectomy plus flutamide versus bilateral orchiectomy and placebo. This trial accrued 222 patients and was reported after a relatively short follow-up. Interestingly, the calculated median survival favored monotherapy over Combined androgen blockade (31 and 23 months, respectively) although the difference was not statistically significant (p = .21). Cyproterone acetate was used in two studies, demonstrating a benefit in the Combined androgen blockade arm.

Eisenberger et al. reported on the largest trial conducted thus far to evaluate the Combined androgen blockade question (NCI INT-0105). This study was a prospectively randomized, double-blinded, placebo-controlled trial evaluating orchiectomy with or without flutamide in 1387 patients. It was conducted by the same investigators involved in INT-0036 and was planned to address the questions posed by its findings. The study was designed to have sufficient statistical power to detect a > 25% survival advantage for the Combined androgen blockade arm, based on the results of the previous study (INT-0036). The follow-up period was approximately 50 months; 70% of patients were dead at the time of the final analysis. The study failed to confirm the initial findings of INT-0036 in support of the Combined androgen blockade hypothesis. The median survival of patients on the Combined androgen blockade arm was 33 months compared to 30 months on the orchiectomy arm (two-sided stratified p = .14, hazard ratio = .91, 90% CI = 0.81-1.01).

The only distinct differences between the two INT trials were the greater proportion of patients with minimal disease (13 versus 20%) and the younger age (median 67 versus 70 years) in the earlier trial. It is unlikely that these differences can explain the disparity in outcome between the studies. Similarly, the main differences between the multinational nilutamide trial and INT-0105 are the choice of nonsteroidal antiandrogen and the size of the studies, which again do not explain the difference in results.

An important observation concerning the multinational nilutamide and INT-0105 studies is the differences in prostate-specific antigen (prostate-specific antigen) changes associated with treatment. Dijkman et al. observed that in 121 of 457 patients, prostate-specific antigen value normalized after 3 months of treatment and that early normalization corresponded to longer survival and time to progression (p < .0001). The percentage of patients with normal prostate-specific antigen at 3 months was significantly higher in the Combined androgen blockade group (p < .001). However, in INT-0105 there was a large difference in the proportion of prostate-specific antigen normalization (< 4.0 ng/mL) between Combined androgen blockade and monotherapy (74 versus 61%, p = .0002) without a concomitant difference in progression-free and overall survival. The observations of INT-0105 fail to support the role of prostate-specific antigen as a surrogate marker for survival in stage D2 patients and may reflect a separate effect on prostate-specific antigen expression mediated by antiandrogens, which is not associated with clinically significant changes in tumor growth. These findings once again underscore the complexity involved in the assessment of prostate-specific antigen for evaluation of therapeutic efficacy in patients with metastatic disease.

Gn-RH Analogue plus Antiandrogens versus Orchiectomy Alone

Orchiectomy was compared to a combination of Gn-RH analogue and antiandrogen in three trials. The selection of two different types of castration in the treatment arms prevents a double-blinded comparison of treatment arms.

The European Organization for Research and Treatment of Cancer (EORTC) conducted a trial (30853) comparing goserelin plus flutamide to bilateral orchiectomy in 327 patients, most of whom had Ml disease. Preliminary analysis with a median follow-up of 30 months revealed no advantage for Combined androgen blockade. After a longer follow-up time, the investigators reported a 7 month benefit (p = .04) in median overall survival for the Combined androgen blockade arm.

The Danish Prostatic Cancer Group (DAPROCA) conducted an identical study around the same time as EORTC 30853, which failed to confirm the survival advantage. The results showed longer overall survival for the monotherapy (leuprolide alone) arm although this was not statistically significant. An evaluation of DAPROCA and EORTC 30853 trials indicated comparable populations and study parameters. Combined analysis of both studies did not result in significant survival difference.

Antiandrogens

Most clinical trials evaluating nonsteroidal compounds employed primarily nilutamide and flutamide in the Combined androgen blockade treatment arm. Except for minor differences in the type and incidence of some adverse effects, Combined androgen blockade regimens with these compounds demonstrate comparable outcome figures. Bicalutamide, a widely used nonsteroidal antiandrogen, has not been evaluated in the context of Combined androgen blockade versus monotherapy in randomized controlled trials. Schellhammer et al. reported on a study comparing four Combined androgen blockade regimens: leuprolide plus flutamide, goserelin plus flutamide, leuprolide plus bicalutamide, and goserelin plus bicalutamide. The most recent analysis indicates no significant overall difference in survival between the four arms. Subset analysis suggests a trend only in survival benefit for leuprolide plus bicalutamide. In view of the nature of this evaluation (subset analysis) this observation should be considered preliminary. Another study from the Italian Prostate Cancer Group compared single-agent bicalutamide given at a dose of 150 mg to the combination of goserelin and flutamide. Very preliminary findings suggest a similar pattern of progression-free and overall survival for the two arms of treatment. The rationale for this comparison is not clear since previous trials showed that single agent bicalutamide was less active than castration alone in both 50- and 150-mg regimens. However, if future analysis of the mature data confirms the preliminary observation, the results of this trial will not be in favor of Combined androgen blockade.

Seven studies used cyproterone acetate in combination with surgical or medical castration. Cyproterone acetate is a steroidal antiandrogen that has not been approved for this use in the United States. No trial using cyproterone acetate reported a significant improvement in survival. In the PCTCG meta-analysis, there appears to be a trend toward decreased survival in populations treated with cyproterone acetate in the combined regimen. Future studies to evaluate the role of cyproterone acetate in the Combined androgen blockade setting are clearly not indicated.

months for the leuprolide plus placebo arm and 48 months for the combination arm. The median survival was 42 and 61 months, respectively. Multivariate analysis of the INT-0036 data indicated that extent of disease represents an important prognostic factor in metastatic prostate cancer. The subset analysis on INT-0036 included only a limited number of patients and therefore should be reviewed as a hypothesis requiring confirmation in specifically designed prospective randomized trials.

Data from EORTC 30853 also suggest that patients with good performance status and minimal disease may benefit the most from Combined androgen blockade. The definition of extent of disease in the EORTC trial is different from the NCI intergroup trials and involves counting the positive areas on bone scan and ignoring the status of visceral involvement. Once again, considering the very small number of patients in this subset category, no formal conclusion can be drawn.

Following the findings in INT-0036 regarding the minimal disease subset, patients in the NCI INT-0105 trial were prospectively stratified by extent of disease. The advantage in progression-free and overall survival observed for the minimal disease subset in INT-0036 was not seen in INT-0105. Unfortunately, despite the large overall number of patients in INT-0105, the number of patients with minimal disease is still limited and prevents definitive statements. However, the Kaplan-Meier curve distributions of progression-free and overall survival in the minimal disease subset in INT-0105 suggest that the large differences seen in the earlier study are questionable. It is important to recognize that none of the studies conducted thus far were designed and sufficiently powered to address the question on the relative value of Combined androgen blockade in the various subsets.

Another way to evaluate treatment-related toxicity is to compare patient dropout from clinical trials. The INT-0105 trial reported that 33 patients with Combined androgen blockade were removed from the study because of drug toxicity, compared to only 10 patients in the placebo arm (p = .003). Higher incidence of dropout was also reported with the use of nilutamide and bicalutamide in Combined androgen blockade regimens.

Several authors claim that response rate was higher and symptoms were controlled earlier with Combined androgen blockade, which may suggest a more favorable quality of life for this arm. No validated quality of life assessment instrument was available during the time most Combined androgen blockade studies were conducted, however, and the information available on quality of life parameters is quite limited in most trials. The only study that prospectively evaluated quality of life in patients undergoing Combined androgen blockade treatment was recently reported by Moinpour et al. This randomized, double-blind, placebo-controlled trial employed an evaluation of the Southwest Oncology Group (SWOG) quality of life questionnaire during the initial 6 months of NCI INT-0105. Data were collected on three treatment-related adverse effects, on physical functioning, and on emotional functioning. Improvement in quality of life over the baseline parameters was seen in both arms but was more pronounced in the placebo group (monotherapy). Patients in the Combined androgen blockade arm reported more diarrhea and worse emotional functioning that were both statistically significant. Thus, the quality of life benefit from orchiectomy in metastatic prostate cancer patients appeared to diminish with the addition of flutamide, possibly because of increased incidence of adverse effects.

Since metastatic prostate cancer is incurable by current therapeutic approaches, the higher incidence of adverse events and reduced quality of life coupled with factors such as cost of treatment should be balanced against an at best marginal overall clinical benefit resulting from this therapeutic approach.

More recent studies of PSA response to ADT have confirmed and amplified those observations. The odds ratio for progression to androgen-refractory disease within 24 months of starting androgen deprivation therapy was almost 15 times higher for patients who did not achieve undetectable PSA. For each unit increase in Gleason score, the cumulative hazard of androgen-refractory progression was nearly 70%. In one cohort of Asian men, nadir prostate specific antigen was the most accurate predictor of disease progression and was independently prognostic of survival; achieving a PSA level of 1.1 ng/mL or less at 6 months after initiation of ADT was the most sensitive and specific predictor of progression at 2 years. Considering the kinetics of PSA rise before ADT compared with the rate of prostate specific antigen decline after ADT also predicted outcome, specifically prostate cancer–specific mortality. If the pre-ADT rise in PSA level was rapid and the decline after ADT was slow, the cancerspecific mortality was significantly worse than for those with slow rises of PSA level before ADT and rapid declines after androgen deprivation therapy.

Almost without exception, those no longer responding to ADT (androgen refractory) remain on ADT. Therefore, factors influencing survival in that disease state should be considered in this discussion. In most cases, available data are based on pretreatment or post-treatment responses to other systemic treatments. Consistently predictive variables (by both univariate and multivariate analysis) of survival in this state include performance status, serum lactate dehydrogenase concentration, serum alkaline phosphatase concentration, hemoglobin level, and prostate specific antigen response to secondary therapy. The survival of men treated on seven sequential chemotherapy protocols at one institution provided an early experience in developing predictive measures. A 50% decline in PSA level in response to chemotherapy was one of the most significant variables predicting survival. A nomogram based on a larger group of patients found the presence of visceral disease, Gleason score, performance status, baseline PSA level, serum lactate dehydrogenase and alkaline phosphatase concentrations, and hemoglobin level useful in modeling prognosis.

Response to androgen blockade

The magnitude and rapidity of the initial response to ADT are strong predictors of the durability of that response.

Table: Therapeutic Approaches to Androgen Deprivation Therapy[*]

DES, diethylstilbestrol; LH, luteinizing hormone; LHRH, luteinizing hormone–releasing hormone.

* Several agents have multiple mechanisms of action.

Ablation of Androgen Sources

Bilateral orchiectomy quickly reduces circulating testosterone levels to less than 50 ng/dL, which, on the basis of this procedure, is considered the castrate range. Within 24 hours of surgical castration, testosterone levels are reduced by more than 90%. The Veterans Administration Cooperative Urological Research Group (VACURG) conducted a series of large clinical trials, demonstrating the clinical effectiveness of surgical castration in reducing pain and performance status in men with advanced disease.

Scrotal (Simple) Orchiectomy

A straightforward outpatient procedure, the simple scrotal orchiectomy can be performed under local anesthesia. At the level of the external ring, each spermatic cord is grasped and infiltrated with 10 mL of 1% lidocaine without epinephrine. This cord block can be performed before the formal skin preparation and draping. After infiltration of the skin overlying the median raphe with 1% lidocaine, a 6- to 8-cm incision is made directly over the median raphe. After the skin incision, electrocautery is used exclusively to transect the other tissue layers, reducing the risk of scrotal hematoma formation. The incision is directed into one hemiscrotum, where the tunica vaginalis is divided and the testicle delivered through the wound. The cord is mobilized above the testicle but below the level of the external ring. The cord structures are divided into two or three equal components, and the cord is ligated with nonabsorbable sutures. I favor double ligation of the proximal cord with two sutures, one of which is a suture ligature. The cord is transected relatively close to the ligatures to limit the amount of nonviable tissue distal to the ligature. Care is taken to examine for any bleeding as a scrotal hematoma after scrotal orchiectomy can be dramatically large. The identical procedure is performed on the contralateral side. The dartos is then reapproximated in the midline, closing each semiscrotal incision at the same time in one layer. The skin is closed with interrupted absorbable sutures. Drains are not used for clean scrotal wounds. Scrotal supports are used for the first several days after surgery, and ice is applied for symptomatic relief.

Subcapsular orchiectomy has been advocated as a technique of androgen deprivation therapy (ADT) that avoids the psychological consequences of an empty scrotum. Because this approach relies on the complete removal of all intratesticular tissue and Leydig cells, it is more dependent on technique to achieve ADT than a simple orchiectomy is. In a properly performed operation, however, the hormonal and cancer responses are indistinguishable from those of a simple, complete orchiectomy.

Antiandrogens

Cyproterone Acetate

The classic steroidal antiandrogen with direct androgen receptor–blocking effects, cyproterone acetate also rapidly lowers testosterone levels to 70% to 80% through its progestational central inhibition. An oral agent, the recommended dose is 100 mg, two to three times per day. Side effects are consistent with the hypogonadal state and include loss of libido, erectile dysfunction, and lassitude. Severe cardiovascular complications can occur in up to 10% of patients, limiting the use of cyproterone acetate. Gynecomastia occurs in less than 20% of men. Rare cases of fulminant hepatotoxicity have been reported. It has been used at doses of 50 to 100 mg/day for the treatment of hot flashes.

Nonsteroidal Antiandrogens

By blocking the testosterone feedback centrally, the nonsteroidal antiandrogens cause LH and testosterone levels to increase. Testosterone levels reach about 1.5 times the normal levels of hormonally intact men. This allows antiandrogen activity without inducing hypogonadism; potency, therefore, can be preserved. However, in clinical trials specifically examining erectile functioning and sexual activity in men receiving flutamide monotherapy, long-term preservation of those domains was only 20%, not much different from men undergoing surgical castration. The peripheral aromatization of increased testosterone to estradiol has been demonstrated after antiandrogen administration, leading to the widely recognized gynecomastia and mastodynia associated with these agents. Gastrointestinal toxicity, most notably diarrhea, is more common with flutamide than with the other nonsteroidal antiandrogens. Liver toxicity, ranging from reversible hepatitis to fulminant hepatic failure, is associated with all nonsteroidal antiandrogens, and periodic monitoring of liver function is required.

Antiandrogen Withdrawal Phenomenon

Patients treated with a combination of an antiandrogen and an luteinizing hormone–releasing hormone agonist can experience a decline in prostate specific antigen (PSA) level and even objective responses with the withdrawal of the antiandrogen from the combination. On the basis of this response, it appears that the antiandrogen is actually exerting agonistic activity on prostate cancer cells. This phenomenon, first described with flutamide has now been demonstrated with all antiandrogens, including cyproterone acetate as well as DES and progestational agents. Declines in prostate specific antigen level are seen within 4 weeks with flutamide withdrawal and within 6 weeks with bicalutamide and nilutamide withdrawal. Between 15% and 30% of patients may have declines in PSA level of more than 50% after antiandrogen withdrawal and have a median duration of 3.5 to 5 months. Objective, measurable tumor responses are observed less commonly. Overall survival has not been shown to be increased in those demonstrating the antiandrogen withdrawal phenomenon compared with those who have not. Clinical trial designs of novel agents must take this phenomenon into consideration, given the possible confounding effects. Prospective criteria to predict who will demonstrate this response have not been established, but it has been recognized that those with rapid PSA responses after androgen ablation have higher rates of antiandrogen withdrawal phenomenon.

It has been postulated that mutations in the androgen receptor may underlie this phenomenon, allowing the antiandrogen to behave like an activator of the androgen receptor. The widely used prostate cancer cell line LNCaP expresses an androgen receptor with a specific point mutation that causes cell proliferation in the presence of hydroxyflutamide; the identical mutation was found in human tumor samples from patients who had remarkable declines in prostate specific antigen level after antiandrogen withdrawal. Similar point mutations in the androgen receptor have been described for bicalutamide to act as an agonist; the structural basis of this mutation, resolved by x-ray crystallography, demonstrates the ability of bicalutamide to bind to the mutant androgen receptor in a fashion similar to dihydrotestosterone (DHT) to the wild-type androgen receptor.

Flutamide

A nonsteroidal antiandrogen, flutamide was the first “pure” antiandrogen. Because of the short half-life (6 hours) of the active metabolite, 2-hydroxyflutamide, this oral agent requires a three-times-a-day dosing schedule, 250 mg per dose. Elimination of hydroxyflutamide is by renal excretion. Unlike with the steroidal antiandrogens, there are no associated side effects of fluid retention or thromboembolism. In a randomized, double-blind study comparing flutamide with DES (3 mg/day) in metastatic prostate cancer, overall survival was significantly shorter with flutamide (28.5 months) than with DES (43.2 months).

Bicalutamide

A nonsteroidal antiandrogen with a long serum half-life (6 days), bicalutamide has a once-per-day dosing schedule and therefore is likely to have better compliance. It is the most potent of the nonsteroidal antiandrogens and the best tolerated. The pharmacokinetics of bicalutamide are not affected by age, renal insufficiency, or moderate hepatic impairment. The R isomer of bicalutamide has about a 30-fold higher binding affinity to the androgen receptor compared with the S isomer and functionally processes the antiandrogen activity. Like the other antiandrogens, bicalutamide is associated with maintenance of serum testosterone levels; in the majority of patients, these remain within the normal range.

Bicalutamide as monotherapy has been most extensively studied, and like the inferiority of flutamide monotherapy to DES, bicalutamide monotherapy at a dose of 50 mg/day was inferior to castration in survival of men with metastatic disease. At higher dose of 150 mg/day, however, bicalutamide monotherapy appears to have efficacy equivalent to that of medical or surgical castration in men with metastatic or locally advanced disease. In these large phase III studies, bicalutamide monotherapy (150 mg/day) had significantly better quality of life in the domains of sexual interest and physical capacity. There was, however, a high rate of gynecomastia (66.2%) and breast pain (72.8%). Of more concern, in men with low-risk, localized prostate cancer, bicalutamide was associated with significantly worse overall survival compared with those on watchful waiting.

Nilutamide

The plasma half-life of nilutamide is 56 hours, and elimination is by hepatic clearance employing the cytochrome P-450 system. Because steady-state plasma levels are achieved in 14 days on once-per-day dosing, dosing recommendations are a single 300-mg daily dose for the first month of treatment followed by a single 150-mg daily dose. About one quarter of men receiving nilutamide therapy will note a delayed adaptation to darkness after exposure to bright illumination. In approximately 1% of patients, nilutamide is also associated with interstitial pneumonitis, which can progress to pulmonary fibrosis. The early effects are usually reversible with cessation of nilutamide. In a small study, there was a suggestion of a role for nilutamide as an effective secondary hormonal agent.

Inhibition of LHRH

LHRH Agonists

The LHRH agonists exploit the desensitization of luteinizing hormone–releasing hormone receptors in the anterior pituitary after chronic exposure to LHRH, thereby shutting down the production of LH and, ultimately, testosterone. The clinical utility of the current LHRH agonists is based on the creation of analogs of native LHRH by amino acid substitutions, particularly position 6 in the peptide, increasing their potency and half-lives ( Table: Structure of LHRH and Therapeutic Analogs ). Pharmacologic depot preparations and osmotic pump devices allow dosing to extend from 28 days to 1 year, respectively ( Table: LHRH Agonists Approved for the Treatment of Prostate Cancer ). In a review of 24 trials involving more than 6600 patients, survival after therapy with an LHRH agonist was equivalent to that of orchiectomy.

Table: Structure of LHRH and Therapeutic Analogs

LHRH, luteinizing hormone–releasing hormone.

Table: LHRH Agonists Approved for the Treatment of Prostate Cancer

LHRH, luteinizing hormone–releasing hormone.

The initial exposure to more potent agonists of LHRH results in a flare of LH and testosterone levels. This phenomenon is seen with all available LHRH preparations and can result in a severe, life-threatening exacerbation of symptoms. The flare, associated with up to a 10-fold increase in luteinizing hormone, may last 10 to 20 days. Fortunately, the co-administration of an antiandrogen functionally blocks the increased levels of testosterone. Although it had been argued that the administration of the antiandrogen should precede the administration of the LHRH agonist by a week, others have found no differences in prostate specific antigen levels with the simultaneous administration of both agents. Given the predictable length of the flare phenomenon, co-administration of antiandrogens is required for only 21 to 28 days.

LHRH Antagonists

The LHRH antagonists bind immediately and competitively to the LHRH receptors in the pituitary, reducing LH concentrations by 84% within 24 hours of administration. The direct antagonistic activity eliminates the LH and testosterone flare, which is a major therapeutic advantage of these agents; there is no need for antiandrogen co-administration. Hormonally naive patients with impending spinal cord compression or severe bone pain for whom surgical castration is not appropriate may uniquely benefit from this class of agents; clinical response has been observed with the LHRH antagonist cetrorelix.

In clinical trials of the luteinizing hormone–releasing hormone antagonist abarelix, testosterone levels dropped quickly, with 34.5%, 60.5%, and 98.1% of men chemically castrate at 2, 4, and 28 days, respectively. Compared with an LHRH agonist and an antiandrogen, abarelix monotherapy was equally effective in achieving castrate levels of testosterone. Ninety percent of men with symptomatic prostate cancer treated in an open-label fashion had improvements in pain or disease-related problems.

Many of the first- and second-generation antagonists induced significant histamine-mediated side effects, complications not as often observed in third- and fourth-generation agents. Nevertheless, severe allergic reactions can occur, even after previously uneventful treatment. Abarelix is approved in the United States for the treatment of advanced prostate cancer in patients who cannot take other hormonal therapies and have refused surgical castration. Given the rare but serious allergic reactions, patients must be monitored for at least 30 minutes after administration.

FSH levels are only partially suppressed by LHRH agonists, and FSH levels are significantly elevated after surgical castration, given the loss of inhibitory feedback. LHRH antagonists reduce both LH and FSH levels. In an androgen-insensitive prostate cancer xenograft model, cetrorelix significantly reduced tumor growth, suggesting that other factors stimulate tumor growth. In men with disease progression after surgical castration, treatment with abarelix reduced FSH levels by nearly 90% but did not meet criteria for PSA response.

Inhibition of Androgen Synthesis

Aminoglutethimide

Aminoglutethimide inhibits the conversion of cholesterol to pregnenolone, an early step in steroidogenesis. Given its inhibition of a very proximal step in adrenal function, aminoglutethimide blocks production of aldosterone and cortisol. As the medical version of a total adrenalectomy, the use of this agent requires replacement of cortisone and fludrocortisone. Side effects include anorexia, nausea, rash, lethargy, vertigo, hypothyroidism, and nystagmus. Clinical responses have been observed in a subset of patients with androgen-refractory prostate cancer treated with aminoglutethimide plus cortisone. In the PSA era, 37% of patients had more than a 50% decline in PSA level with treatment by aminoglutethimide (1000 mg/day) and hydrocortisone acetate (40 mg/day), with median response times lasting 9 months.

Ketoconazole

An orally active, broad-spectrum azole antifungal agent, ketoconazole interferes with two cytochrome P-450–dependent pathways: inhibition of 14-methylation in the conversion of lanosterol to cholesterol and blockade of 17,20-desmolase, affecting the conversion of C21 to C19 steroids. On the basis of the observation that some patients taking the drug developed gynecomastia, investigations of its effects on steroid synthesis demonstrated loss of adrenal steroid synthesis and testosterone synthesis by Leydig cells. The effects were rapid, with testosterone levels dropping to the castrate level within 4 hours of administration in some cases; the effects were also immediately reversible, indicating that dosing must be continuous to maintain low testosterone levels (400 mg every 8 hours).

Early experience with ketoconazole in the treatment of prostate cancer showed this agent to be tolerable, durable, and effective and palliative for those whose first-line androgen ablation therapy had failed. Although it is effective in rapidly bringing testosterone levels into the castrate range, with continuous treatment with ketoconazole in the otherwise hormonally intact individual (no other surgical or chemical ADT), testosterone levels begin to rise and can reach low-normal ranges within 5 months of therapy. Therefore, ketoconazole is currently used for men with androgen-refractory prostate cancer, often as the first or second agent in so-called secondary hormonal manipulation. In addition to gynecomastia (caused by alterations in testosterone-to-estradiol ratios), ketoconazole is associated with lethargy, weakness, hepatic dysfunction, visual disturbance, and nausea. Because of the adrenal suppression, ketoconazole is usually given with hydrocortisone (20 mg, twice per day).

Mechanisms of androgen axis blockade

There are four general forms of androgen deprivation therapy: ablation of androgen sources, inhibition of androgen synthesis, antiandrogens, and inhibition of LHRH or LH.

Bilateral orchiectomy reduces testosterone by 90% within 24 hours of surgery.

Nonsteroidal antiandrogens cause LH and testosterone levels to increase.

Serious liver toxicity is a possible side effect of all antiandrogens.

Antiandrogens can act agonistic on some tumors; antiandrogen withdrawal results in decline of PSA level in 15% to 30% of patients.

Bicalutamide 150-mg monotherapy appears to have efficacy equivalent to that of medical or surgical castration for locally advanced or metastatic prostate cancer.

All LHRH agonists induce a testosterone increase on initial exposure. Co-administration of an antiandrogen functionally blocks the effects of testosterone.

Molecular biology of androgen axis

Androgen deprivation is one of the most effective therapies against any solid tumor; unfortunately, with time, almost all prostate cancers will become androgen refractory.

All current forms of ADT function by either lowering levels of circulating androgens or blocking the binding of androgen to the androgen receptor.

Almost all androgen-refractory prostate cancer remains sensitive to androgen; therefore, ADT should continue in hormone-refractory disease.

Androgens produced by the adrenal gland, androstenedione and dehydroepiandrosterone, are stimulated by adrenocorticotropic hormone (ACTH) released by the pituitary gland in response to corticotropin-releasing factor. Adrenal androgens do negatively feed back on ACTH secretion; cortisol acts as the feedback signal. Adrenal androgens are relatively weak compared with testosterone and DHT and are almost entirely bound to albumin ( Table: Major Circulating Androgens ). Adrenal androgens remain normal in men who have undergone orchiectomy, and adrenal androgens are insufficient to maintain prostatic epithelium in such men.

Table: Major Circulating Androgens

The increased number of men being prescribed androgen ablation therapy much earlier in the course of their disease allows the chronic manifestations of the hypogonadal state to emerge. Widespread androgen ablation therapy applied to an increasingly aging population, already predisposed to loss of bone mineral density, has created an epidemic of osteopenia and osteoporosis. Fragile bones increase the risk of skeletal fracture. More than half of men meet the bone mineral density criteria for osteopenia or osteoporosis — defined as more than 2.5 standard deviations below an age-specific reference mean — before the initiation of androgen deprivation therapy (ADT). The longer a man receives ADT, the greater the risk of fracture. After 5 years of androgen deprivation therapy, 19.4% of men experienced fractures compared with 12.6% of controls; with more than 15 years, cumulative incidence of fractures was 40% compared with 19% of non-castrate controls. It has been estimated that 4 years of ADT will place the average man in the osteopenia range. Rarely discussed even 10 years ago, skeletal health is now becoming a major concern of patients and their physicians.

Treatment of osteoporosis begins with recognition. Bone mineral density of the hip, as measured by dual energy x-ray absorptiometry, should be considered for all men anticipated to be prescribed long-term androgen deprivation therapy. Smoking cessation, weight-bearing exercise, and vitamin D and calcium can help improve bone mineral density. Prevention of osteoporosis in men receiving ADT has been demonstrated in controlled studies with the bisphosphonate pamidronate; bone mineral density actually increased in men receiving ADT with the considerably more potent bisphosphonate zoledronic acid. Bisphosphonate therapy should be considered in any man with evidence of osteopenia or osteoporosis. Transdermal estradiol also increases bone mineral density in men with prostate cancer. Not surprisingly, serum testosterone and estradiol levels were much lower in men receiving luteinizing hormone–releasing hormone (LHRH) agonists compared with those receiving a nonsteroidal antiandrogen; interestingly, markers of bone turnover were significantly higher in men receiving LHRH agonists compared with those receiving a nonsteroidal antiandrogen, suggesting that nonsteroidal antiandrogens may help maintain bone mineral density.

Hot Flashes

For more than 100 years, hot flashes (also called hot flushes, vasomotor symptoms) have been recognized as a side effect of androgen ablation; in 1896, Cabot mentioned “uncomfortable flushes of heat, similar to those experienced by women at the time of menopause” in men undergoing castration for prostatic enlargement. Described as a subjective feeling of warmth in the upper torso and head followed by objective perspiration, hot flashes are not life-threatening but are among the most common side effects of androgen ablation, affecting between half and 80% of patients. Occurring spontaneously and precipitated by changes in body position, ingestion of hot liquids, or changes in environmental temperature, the exact etiology of hot flashes remains undefined. The proposed mechanisms include increases in hypothalamic adrenergic concentrations, alterations in β-endorphins, and involvement of calcitonin generelated peptides acting on the thermoregulatory center in the hypothalamus. Hot flashes generally decrease in both frequency and intensity over time but can persist in some men.

Treatment of hot flashes should be reserved for those who find them bothersome. Just as hot flashes are a consequence of alterations in the hormonal milieu, the mainstay of treatment has been based on efforts to influence that milieu. In a double-blind, placebo-controlled, cross-over study, the progestational agent megestrol acetate (20 mg, twice per day) significantly reduced the frequency of hot flashes. The dose can be reduced to 5 mg twice daily, which may help reduce the appetitestimulating effect of this agent. The efficacy of cyproterone acetate is based on its progestational effects. Dosing should start at 50 mg/day and be titrated to 300 mg/day. Estrogenic compounds, such as low-dose DES and transdermal estradiol, appear to be the most effective treatment, with up to 90% partial or complete resolution of symptoms. With estrogen compounds, however, the cure may be worse than the disease; painful gynecomastia and thromboembolic effects have limited the utility of this approach. Clonidine, a centrally acting α agonist that decreases vascular reactivity, has been used with mixed results; in a placebocontrolled study, transdermal clonidine did not significantly decrease hot flashes. Antidepressant agents, particularly the selective serotonin reuptake inhibitor venlafaxine (12.5 mg, twice daily), have reduced hot flashes in more than 50% of men.

Sexual Dysfunction (Erectile Dysfunction and Loss of Libido)

The effects of ADT on sexual function are profound, as first described by Huggins: “Sexual desire and penile erections were absent in all cases following castration”. Loss of sexual functioning is not inevitable, however; up to 20% of men receiving ADT are able to maintain some sexual activity. Specifically, between 10% and 17% of men undergoing androgen deprivation therapy can maintain an erection adequate for intercourse. Libido is more severely compromised, with approximately 5% of men maintaining a high level of sexual interest with ADT. Sexual desire is inversely related to the duration of androgen deprivation. Loss of penile volume, penile length, nocturnal penile tumescence, and, for those undergoing medical ADT, testicular volume are common.

Treatment for loss of libido is extremely difficult if not impossible for those receiving androgen deprivation therapy. Likewise, medical treatments, such as oral phosphodiesterase type 5 inhibitors, or local treatments, such as intracavernosal injections of alprostadil, can still be effective in selected patients, but patients may decide not to use them during the long term. If there is any fairness in the negative effects of ADT on sexual function, it is the decline in both libido and erectile functioning; despite no erections or desire, the majority of patients have little or no problem with their lack of sexual functioning.

Cognitive Function

In both men and women, the hypogonadal state is associated with declines in cognitive functioning. Testosterone supplementation improves verbal fluency; other controlled studies have found no effect of such supplementation on memory. In a small study, men with prostate cancer randomized to androgen deprivation therapy performed worse in cognitive studies compared with men with prostate cancer under surveillance; the declines were associated with tasks requiring complex information processing. Compared with tests for other cognitive domains, tests for spatial ability uniquely declined in men receiving intermittent hormone therapy. In men receiving neoadjuvant ADT before radiotherapy, cognitive functioning declined. Unfortunately, the studies examining the effects of androgen deprivation therapy on cognitive functioning have been small and underpowered.

Not surprisingly, given the many side effects of ADT, quality of life worsens, specifically in men receiving flutamide in addition to castration, compared with placebo, in the domain of emotional functioning. A short course of androgen deprivation therapy (36 weeks) increased depression and anxiety scores on formal neuropsychological evaluations; major depressive disorder was prevalent in 12.8% of men receiving ADT, 8 times greater than the national rate and 32 times the rate of men older than 65 years. Finally, psychological distress accounted for approximately one third of declines in fatigue severity scale in men undergoing androgen deprivation therapy.

Changes in Body Habitus

A loss of muscle mass and increase in percentage of fat body mass are common in men undergoing androgen deprivation therapy. After 1 year of ADT, the mean overall weight increases 1.8% to 3.8%, which translates into about 5 pounds for a 200-pound man. One study found weight increased a median of 6 kg (13.2 lb), with a range of 3 to 15 kg (6.6 to 33 lb). Since lean body mass usually decreases by the same magnitude, the weight gain is largely due to an increase in fat mass. The average increase in fat mass ranges from 9.4% to 23.8%. As noted by Huggins, androgen deprivation therapy is associated with an increase in appetite, and low testosterone level is associated with increased insulin level and abdominal girth.

The Cancer Prevention Studies I and II (1959-1972 and 1982-1996, respectively) were large population-based studies of obesity and the risk of cancer mortality. In both studies, the risk of death from prostate cancer in obese men was 34% (Study I) and 36% (Study II) compared with men of normal weight. Furthermore, men older than 65 years who engaged in vigorous exercise more than 3 hours per week had a 70% reduction in prostate cancer–specific death. The body composition changes associated with androgen deprivation therapy may portend a worse prognosis for men with prostate cancer. Regular vigorous exercise may help patients limit the accumulation of fat and even prevent prostate cancer progression.

Gynecomastia

Depending on the agents used in ADT, alterations in breast tissue are common. Gynecomastia, an increase in breast tissue, and mastodynia, or breast tenderness, may occur together or independently. Estrogenic compounds, such as diethylstilbestrol (DES), induce gynecomastia in 40% of patients. Likewise, the peripheral conversion of testosterone to estradiol associated with the antiandrogens induces gynecomastia at high rates; 66.3% of men taking 150 mg of bicalutamide developed gynecomastia and 72.7% developed mastodynia.

Prophylactic radiation therapy (10 Gy) has been used to prevent or to reduce painful gynecomastia as a result of DES or antiandrogen therapy. Radiation has no benefit once gynecomastia has begun. Liposuction and subcutaneous mastectomy have been used to treat established gynecomastia. The selective estrogen receptor modulator tamoxifen has been used to treat mastodynia.

Anemia

The anemia associated with ADT is normochromic, normocytic, and it is common; 90% of men receiving combined androgen blockade experienced declines in hemoglobin concentration of at least 10%. Although anemia can be further complicated by tumor growth in the marrow space, compromising hematopoiesis, even men with nonmetastatic prostate cancer experience anemia with androgen deprivation therapy. Unfortunately, anemia (defined as hemoglobin level below 12 g/dL) is associated with a shorter survival in those anemic before initiation of ADT. Declines in hemoglobin concentration begin within 1 month of androgen deprivation therapy initiation and continue for 24 months. Compensatory mechanisms limit the symptomatic effects of anemia to a small subset (13%) of men.

The etiology of anemia is thought to be secondary to lack of testosterone stimulation of erythroid precursors and a decrease in erythropoietin production. In an animal model, however, erythropoietin levels increased after androgen deprivation therapy. Whatever the etiology, clinically, patients respond to recombinant human erythropoietin. The anemia is reversible after ADT is stopped, but it may take up to a year.

Key points: complications of androgen ablation

The side effects of androgen deprivation therapy (ADT) include osteoporosis, hot flashes, sexual dysfunction, cognitive function alterations, changes in body habitus, gynecomastia, and anemia. These side effects can be progressive but are responsive to other treatments.

Liarozole, a novel imidazole derivative, is the first retinoic acid metabolism-blocking agent (RAMBA) to be developed as differentiation therapy for human solid tumors. Most importantly, the drug has been shown to demonstrate anticarcinogenic and antitumor effects. Preclinical studies of liarozole have shown that it inhibits the growth of androgen-independent tumors, along with others, by inhibiting 4-hydroxylase, a cytochrome P450-dependent enzyme that is involved in retinoic acid catabolism. A recent study compared the ability of these two drugs to induce prostate-specific antigen (PSA) response in patients with metastatic prostate cancer that is progressing in response to first-line endocrine therapy. The multicenter, randomized trial consisted of 321 patients who had been recruited from 53 centers in 10 countries. Median age at the beginning of the trial was 72 years, with a range of 46 to 88 years. All patients except one were white. Identified as prognostic factors for survival were baseline hemoglobin, alkaline phosphatase, PSA, duration of response to first-line treatment, and performance status. Because most patients with prostate cancer do not present assessable lesions, it is difficult to evaluate objective tumor response. As a result, prostate-specific antigen (PSA) was used in this study as a marker for tumor response.

Liarozole was started at 150 mg twice daily and then increased 300 mg twice daily for the remainder of the treatment. The cyproterone acetate (CPA) dose used was 100 mg twice daily from the start of the study and remained the same unless dosage adjustments were necessary according to prescribing information. Treatment continued until clinical progression was shown or a serious adverse event occurred. Patients were followed up until death. The trial was analyzed after 232 deaths.

Prostate-specific antigen (PSA) responders were more prevalent in the liarozole group (20%) than in the cyproterone acetate group (4%), p < 0.001. PSA stabilization occurred in 64% of patients in the liarozole group. Changes indicative of continuous progression were observed in 17% of patients treated with liarozole, in contrast to 40% of patients in the cyproterone acetate group. The response was not affected by previous use of antiandrogens in either treatment group.

Prostate-specific antigen (PSA) response occurred by week 12 in 90% of responding patients. The median time to progression was 4.6 months in the liarozole group and 3.6 months in the cyproterone group. Patients who had a PSA response experienced a median survival of 25 months. Those who experienced stabilization survived for 14 months, and patients with continuous progression survived for 7 months. PSA responders had a 57% lower risk of dying as compared with nonresponders.

When comparing the two drugs, after adjustment for baseline prognostic factors, the study showed that patients treated with liarozole survived longer and had a 26% lower risk of dying than did patients on cyproterone acetate. Liarozole treatment resulted in a significantly better PSA response (20% of patients compared with 4% of the cyproterone group). Also, PSA stabilization was observed in 64% of the liarozole group. Participants in both groups of the trial reported various adverse events. In the liarozole group, the most common problems were dry skin, pruritus, rash, nail disorders, and hair loss. Patients undergoing cyproterone acetate treatment suffered from edema, nausea, vomiting, and fatigue. For the most part, these conditions were mild to moderate. Adverse events caused withdrawal from treatment for 88 patients in the liarozole group and 63 patients in the cyproterone acetate group. Most of the withdrawals occurred because of cancer-related events such as skin disorders, nausea, and vomiting.

Patients with metastatic prostate cancer usually complain of bone pain due to skeletal involvement. Advanced prostate cancer patients will also present with signs and symptoms of lymphadenopathy, lower extremity edema, renal failure, visceral metastases, anemia and cachexia. Prostate cancer and these accompanying medical conditions can lead to a lot of pain and poor performance status.

In conclusion, this trial shows that prostate-specific antigen (PSA) response is an effective way to measure the clinical benefits of prostate cancer therapies. Patients who experienced this response lived longer, had less pain, and an improvement in quality of life. Liarozole was shown to be more effective than cyproterone acetate in achieving PSA response and in treating relapsed prostate cancer.

And saw palmetto berry extract, listed by Consumer Reports in the US as a potentially helpful herb, could be just what the doctor ordered.

As many as a third of all men over 50 may suffer from benign prostate hyperplasia, experts estimate. The condition is not cancerous and simply means that the tissue of the prostate is inflamed and swollen.

Saw palmetto berry extract can help the tissue to shrink, allowing for more regular urination patterns – and with few side effects, as long as you use it with a doctor’s help, experts say.

How does it work? No one is exactly sure, but herbalists have an idea.

“It seems to affect the hormone levels in the genital area,” says Kara Dinda, director of education for the American Botanical Council in Austin, Texas.

And while the effects of the herb on men’s prostates seem fairly well documented, its effect on women is not known. Since hormones may be affected, it’s especially important that pregnant and lactating women not use the herb.

Use of this herb, which derives from the berries of the dwarf palmetto tree which is grown largely in Florida, dates back to the 1700s among Native Americans. Rigorous studies supporting use of the herb are far more recent.

According to an article in the Minneapolis Star Tribune, for example, a 1996 study of 1,098 men in the US showed that saw palmetto berry extract is at least as effective as a popular prescription drug – and produces fewer side effects, including impotence. And The Daily Telegraph reports that close to 90 per cent of men in Germany with benign prostate hyperplasia are treated with plant extracts, and saw palmetto berry extract tops the list.

One concern among doctors has been that use of the herb or a product containing it might affect PSA levels, by which prostate cancer can be diagnosed. But an editorial in Urology said that US herb specialist Varro Tyler and a UCLA urologist showed that use of the herb did not affect any tests of the prostate, including the PSA.

Side effects? They’re relatively minor: stomach problems, headaches and, with large doses, diarrhea.

One caveat: A Boston Globe story reported that a 1998 review of the herb suggested that other new prostate medications may in fact be more effective than saw palmetto berry extract.

What To Do

This herb sounds promising. Men should ask their GP for further information, however. “Herbs produce chemicals,” says Erica Kipp, manager of the Plant Research Laboratory for the New York Botanical Garden. “I think people have the misconception that anything from a plant is natural and good and benign – and this is not necessarily the case.”